Formulation of a mmaA4 gene deletion mutant of mycobacterium bovis BCG in cationic liposomes significantly enhances protection against tuberculosis

Steven C. Derrick, Dee Dao, Amy Yang, Kris Kolibab, William R. Jacobs, Sheldon L. Morris

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

A new vaccination strategy is urgently needed for improved control of the global tuberculosis (TB) epidemic. Using a mouse aerosol Mycobacterium tuberculosis challenge model, we investigated the protective efficacy of a mmaA4 gene deletion mutant of Mycobacterium bovis BCG (ΔmmaA4BCG) formulated in dimethyl dioctadecyl ammonium bromide (DDA) - D(+) trehalose 6,6 dibenenate (TDB) (DDA/TDB) adjuvant. In previous studies, deletion of the mmaA4 gene was shown to reduce the suppression of IL-12 production often seen after mycobacterial infections. While the non-adjuvanted ΔmmaA4BCG strain did not protect mice substantially better than conventional BCG against a tuberculous challenge in four protection experiments, the protective responses induced by the ΔmmaA4BCG vaccine formulated in DDA/TDB adjuvant was consistently increased relative to nonadjuvanted BCG controls. Furthermore, the ΔmmaA4BCG-DDA/TDB vaccine induced significantly higher frequencies of multifunctional (MFT) CD4 T cells expressing both IFNγ and TNFα (double positive) or IFNγ, TNFα and IL-2 (triple positive) than CD4 T cells derived from mice vaccinated with BCG. These MFT cells were characterized by having higher IFNγ and TNFα median fluorescence intensity (MFI) values than monofunctional CD4 T cells. Interestingly, both BCG/adjuvant and ΔmmaA4BCG/adjuvant formulations induced significantly higher frequencies of CD4 T cells expressing TNFα and IL-2 than nonadjuvanted BCG or ΔmmaA4BCG vaccines indicating that BCG/adjuvant mixtures may be more effective at inducing central memory T cells. Importantly, when either conventional BCG or the mutant were formulated in adjuvant and administered to SCID mice or immunocompromised mice depleted of IFNγ, significantly lower vaccine-derived mycobacterial CFU were detected relative to immunodeficient mice injected with non-adjuvanted BCG. Overall, these data suggest that immunization with the ΔmmaA4BCG/adjuvant formulation may be an effective, safe, and relatively inexpensive alternative to vaccination with conventional BCG.

Original languageEnglish (US)
Article numbere32959
JournalPloS one
Volume7
Issue number3
DOIs
StatePublished - Mar 19 2012

Fingerprint

Mycobacterium bovis BCG
T-cells
gene deletion
Gene Deletion
Mycobacterium bovis
Trehalose
tuberculosis
Liposomes
adjuvants
Tuberculosis
Genes
Vaccines
mutants
trehalose
bromides
T-lymphocytes
mice
Interleukin-2
T-Lymphocytes
vaccines

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Formulation of a mmaA4 gene deletion mutant of mycobacterium bovis BCG in cationic liposomes significantly enhances protection against tuberculosis. / Derrick, Steven C.; Dao, Dee; Yang, Amy; Kolibab, Kris; Jacobs, William R.; Morris, Sheldon L.

In: PloS one, Vol. 7, No. 3, e32959, 19.03.2012.

Research output: Contribution to journalArticle

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